Oral manifestations of HIV-infection in patients based on CD4+ T-lymphocyte counts

Objective - analysis and generalization of the available data on the manifestations of human immunodeficiency virus in the oral cavity depending on the number of CD4+ T-lymphocytes in the blood. Materials and methods. A search of clinical studies, systematic reviews, and online meta-analyses was conducted from 2004-2023 in the PubMed, Elsiever, Scopus, Cochrane, and Elibrary databases, which described oral manifestations of HIV infection as a function of CD4+ T-lymphocyte count. Results. Pseudomembranous candidiasis, hairy leukoplakia, Kaposi's sarcoma, and non-Hodgkin's lymphoma develop against a background of severe immunodeficiency when the CD4+ T-lymphocyte count is <200 cells/μL blood. Kaposi's sarcoma also develops in people with a high CD8+ T-lymphocyte count (>1000 cells/μL of blood) or with a low CD4+ to CD8+ ratio (CD4+:CD8+ ≤0.5). Non-Hodgkin's lymphoma develops not only with CD4+ T-cells <200/μL, but also with a high number of CD8+ T-cells (≥2000 cells/μL of blood). Specific periodontal disease develops with moderate to severe immunodeficiency (CD4+ T-cells 200-500 cells/μL of blood). Necrotic ulcerative gingivitis is more often seen in severe immunodeficiency (CD4+ T-lymphocytes <200 cells/μL). Conclusion. The development of pseudomembranous candidiasis (p<0,05), "hairy" leukoplakia (p<0,01), Kaposi sarcoma (p<0,0001) statistically significantly correlates with CD4+ T-lymphocyte count <200 cells/μl blood. In addition, the development of Kaposi's sarcoma, in addition to the low number of CD4+ T-cells, is affected by a high number of CD8+ cytotoxic lymphocytes >1000 cells/μL (p=0.0003) and a low CD4+:CD8+ ratio ≤0.5 (p<0.0003), which is statistically significant.

1. The National Association of Specialists of the Ministry of Health of the Russian Federation for the prevention, diagnosis and Treatment of HIV infection. Clinical recommendations: HIV infection in adults. 2020. 10 p.. URL: https://cr.minzdrav.gov.ru/recomend/79_1

2. Radzikhovskaya M.V., Moskvicheva M.G., Kafeeva E.I. Regulatory support for the organization of medical care for patients with HIV infection at the federal and regional levels (historical overview). Ural Medical Journal. 2018;(4):119-125 (in Russ.). DOI: 10.25694/URMJ.2018.04.052. EDN: UTKFES.

3. Zhu L. Classification and diagnostic criteria for oral lesions in HIV infection. EC-Clearinghouse on oral problems related to HIV Infection and WHO Collaborating Centre on oral manifestations of the immunodeficiency virus. Oral Pathol Med. 2013;22(7):289-291.

4. Berberi A., Noujeim Z. Epidemiology and relationships between CD4+ counts and oral lesions among 50 patients infected with human immunodeficiency virus. J Int Oral Health. 2015;7(1):18-21.

5. Ruterbusch M., Pruner K.B., Shehata L., Pepper M. In vivo CD4(+) T-cell differentiation and function: revisiting the Th1/Th2 paradigm. Annu Rev Immunol. 2020;38:705-725. DOI: 10.1146/annurev-immunol-103019-085803.

6. Dang A.T., Cotton S., Sankaran-Walters S., Li C.S., Lee C.Y., Dandekar S., Paster B.J., George M.D. Evidence of an increased pathogenic footprint in the lingual microbiome of untreated HIV infected patients. BMC Microbiol. 2012;12:153-155. DOI: 10.1186/1471-2180-12-153.

7. Gannepalli A., Krishna A.B., Baghirath P.V., Vinay B.H., Khaled S., Anjum B. Oral manifestations in HIV-TB сo-infected patients and their correlation with CD4 count in Telangana state, India. J Int Soc Prev Community Dent. 2020;10(1):21-35. DOI: 10.4103/jispcd.JISPCD_448_18.

8. Balaji T.M., Varadarajan S., Sujatha G., Muruganandhan J., Shanmugapriya R., Raj A.T., Patil S., Fageeh H.I., Fageeh H.N., Malik N.H., Awan K.H. Necrotizing periodontal diseases in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy: a review. Dis Mon. 2021;67(9):101168. DOI: 10.1016/j.disamonth.2021.101168.

9. Li S., Su B., He Q.S., Wu H., Zhang T. Alterations in the oral microbiome in HIV infection: causes, effects and potential interventions. Chin Med J. 2021;134:2788-2798. DOI: 10.1097/CM9.0000000000001825.

10. Elovikova T.M., Gajsina E.F., Prihodkin A.S. Use of antibacterial drugs for the treatment of aggressive periodontitis. Literature review. Problemy stomatologii. 2019;415(1):10-15 (in Russ.). DOI: 10.18481/2077-7566-2018-15-1-10-15. EDN: EQEZHC.

11. KHairova YA.R., Skorodelova M.I., Nikol'skaya M.V. Opportunistic infections in HIV infection. Medicina i zdravoohranenie. 2021;(2):69-72 (in Russ.)

12. Davleeva B.A. Modern aspects of the pathogenesis and treatment of oral candidiasis. Vestnik KazNMU. 2014;(1):32-36 (in Russ.). EDN: DLPQVE.

13. Aftaeva L.N., Mel'nikov V.L., Votolkina S.V., Sudapina A.R., Nikol'skaya M.V. Features of HIV infection in adults. Siberian scientific medical journal. 2020;(4):86-90 (in Russ.). DOI: 10.15372/SSMJ20200412. EDN: CBYVAE.

14. Prozherin S.V., Podymova A.S., Ryamova E.P. Clinical markers of severe immunosuppression in patients with HIV infection in the Sverdlovsk region on the example of hairy leukoplakia. Klinicheskaya dermatologiya i venerologiya. 2017;16(6):54-61 (in Russ.). DOI: 10.17116/klinderma201716654-6.

15. Gileva O.S, Sadilova V.A. Periodontal disease in HIV-infected patients: prevalence and features of clinical manifestations depending on adherence to antiretroviral therapy. Permskij medicinskij zhurnal. 2013;30(2):34-42 (in Russ.). EDN: QAQOKD.

16. Atanova I.A. HIV-associated non-Hodgkin's lymphomas. Vestnik soveta molodyh uchyonyh i specialistov Chelyabinskoj oblasti. 2019;4(27):3-8 (In Russ.). EDN: JXBSDE.

17. Phiri R., Feller L., Blignaut E. The severity, extent and recurrence of necrotizing periodontal disease in relation to HIV status and CD4+ T-cell count. J Int Acad Periodontol. 2010;12(4):98-103.

18. Zhu J. T-helper cell differentiation, heterogeneity and plasticity. Cold Spring Harb Perspect Biol. 2018;10(10):a030338. DOI: 10.1101/cshperspect.a030338.

19. Zhu X., Zhu J. CD4 T helper cell subsets and related human immunological disorders.Int J Mol Sci. 2020;21(21):8011. DOI: 10.3390/ijms21218011.

20. Kunkl M., Frascolla S., Amormino C., Volpe E., Tuosto L. T helper cells: the modulators of inflammation in multiple sclerosis. Cells. 2020;9(2):482. DOI: 10.3390/cells9020482.

21. Stockinger B., Veldhoen M. Differentiation and function of Th17 T cells. Curr Opin Immunol. 2007;19:281-286. DOI: 10.1016/j.coi.2007.04.005.

22. Heron S.E., Elahi S. HIV infection and compromised mucosal immunity: oral manifestations and systemic inflammation. Front Immunol. 2017;8:241-245. DOI: 10.3389/fimmu.2017.00241.

23. Schreiber F., Arasteh J.M., Lawley T.D. Pathogen resistance mediated by IL-22 signaling at the epithelial-microbiota interface. J Mol Biol. 2015;427:3676-3682. DOI: 10.1016/j.jmb.2015.10.013.

24. Song W., Craft J. T follicular helper cell heterogeneity: time, space and function. Immunol Rev. 2019;288(1):85-96. DOI: 10.1111/imr.12740.

25. Mason M.R., Chambers S., Dabdoub S.M., Thikkurissy S., Kumar P.S. Characterizing oral microbial communities across dentition states and colonization niches. Microbiome. 2018;6(1):67. DOI: 10.1186/s40168-018-0443-2.

26. Gruffaz M., Zhang T., Marshall V., Gonçalves P., Ramaswami R., Labo N., Whitby D., Uldrick T.S., Yarchoan R., Huang Y., Gao S.J. Signatures of oral microbiome in HIV-infected individuals with oral Kaposi's sarcoma and cell-associated KSHV DNA. PLoS Pathog. 2020;16(1):e1008114. DOI: 10.1371/journal.ppat.1008114.

27. Li J., Chang S., Guo H., Ji Y., Jiang H., Ruan L., Du M. Altered salivary microbiome in the early stage of HIV infections among young chinese men who have sex with men (MSM). Pathogens. 2020;9(11):960. DOI: 10.3390/pathogens9110960.

28. Yang L., Dunlap D.G., Qin S., Fitch A., Li K., Koch C.D., Nouraie M., DeSensi R., Ho K.S., Martinson J.J., Methé B., Morris A. Alterations in oral microbiota in HIV. Am J Respir Crit Care Med. 2020;201(4):445-457. DOI: 10.1164/rccm.201905-1016OC.

29. Bayahmetova A.A., Ekesheva A.A. The study of periodontopathogenic microflora of periodontal pockets in periodontitis by molecular genetic method. Nauka i mir. 2016;3(31):73-76 (In Russ.). EDN: VPRNKD.

30. FilinaYu.S., Shatokhin A.I., Volchkova E.V., NesvizhskiyYu.V., Pak S.G. Antimycotic therapy impacton oral mucosa Candida species composition in HIV-infected patients. Stomatologiya. 2018;97(6):28-33 (in Russ.). DOI: 10.17116/stomat20189706128. EDN: YROPDN.

31. Zaharov A.A., Il'ina N.A. Analysis of the microflora of the oral cavity of examined people with various diseases. Uspekhi sovremennogo estestvoznaniya. 2007;12(3):141-143 (in Russ.). EDN: IJMAUF.

32. Saharuk N.A. Microbial flora of the oral cavity in normal and pathological conditions. Morphology of fungi of the genus Candida. Vestnik VGMU. 2008;7(2):2-11 (in Russ.)

33. Tsarev V.N., Nikolaeva E.N., YAgodina E.V., Trefilova YU.A., Ippolitov E.V. Molecular methods for diagnosing gingivitis and periodontitis in HIV-infected patients. Clinical laboratory diagnostics. 2016;61(1):54-59 (in Russ.). EDN: VOTJZV.

34. Azatyan V.Yu. Influence of highly active antiretroviral therapy on the mucosa of the mouth and periodont in HIV-infection. Vestnik stomatologii i chelyustno-licevojhirurgii. 2019;15(4):26-30 (in Russ.)

35. Ermuhanova G.T., Dzhandauletova N.B., Karkimbaeva G.A., Ermuhanova N.T. Clinical course of manifestations of HIV infection in the oral cavity in children.Int Sci Pract Conf. 2017;5(18):35-41 (in Russ.)

36. Ottria L., Lauritano D., Oberti L., Candotto V., Cura F., Tagliabue A., Tettamanti L. Prevalence of HIV-related oral manifestations and their association with HAART and CD4+ T cell count: a review. J Biol Regul Homeost Agents. 2018;32(2.1):51-59.

37. Garcia S.A., Guzman N. Acquired immune deficiency syndrome CD4+. Count. Stat Pearls. 2022;1(1): 130-132.

38. Patil S., Majumdar B., Sarode S.C., Sarode G.S., Awan K.H. Oropharyngeal candidosis in HIV-infected patients-an update. Front Microbiol. 2018;9:980. DOI: 10.3389/fmicb.2018.00980.

39. Vazquez J.A. Therapeutic options for the management of oropharyngeal and esophageal candidiasis in HIV/AIDS patients. HIV Clin Trials. 2015;1(1):47-59. DOI: 10.1310/T7A7-1E63-2KA0-JKWD.

40. Polyanskaya L.N. Features of the manifestations of HIV infection in the oral cavity. Sovremennaya stomatologiya. 2017;1(1):60-63 (in Russ.). EDN: YGWQHJ.

41. Mihed T.M., Krasavcev E.L., Red'ko D.D. Oral candidias is in HIV-infected patients. Problemy zdorov'ya i ekologii. 2010;(1):43-47 (In Russ.). DOI: 10.51523/2708-6011.2010-7-1-10.

42. Repentigny L., Lewandowski D., Jolicoeur P. Immunopathogenesis of oropharyngeal candidiasis in human immunodeficiency virus infection. Clin Microbiol Rev. 2004;17(4):729-759. DOI: 10.1128/CMR.17.4.729-759.2004.

43. Kerdpon D., Pongsiriwet S., Pangsomboon K., AIamaroon L., Kampoo K., Sretrirutchai S., Geater A., Robison V. Oral manifestations of HIV infection in relation to clinical and CD4 immunological status in northern and southern patients. Oral diseases. 2004;10(3):138-144. DOI: 10.1046/j.1601-0825.2003.00990.x.

44. De Almeida V.L., Lima I.F.P., Ziegelmann P.K., Paranhos L.R., De Matos F.R. Impact of highly active antiretroviral therapy on the prevalence of oral lesions in HIV-positive patients: a systematic review and meta-analysis.Int J Oral Maxillofac Surg. 2017;46(11):1497-1504. DOI: 10.1016/j.ijom.2017.06.008.

45. Kreuter A., Wieland U. Oral hairy leukoplakia: a clinical indicator of immunosuppression. CMAJ. 2011;183(8):932.

46. Hall L.D., Eminger L.A., Hesterman K.S., Heymann W.R. Epstein-Barr virus: dermatologic associations and implications: part I. Mucocutaneous manifestations of Epstein-Barr virus and nonmalignant disorders. J Am Acad Dermatol. 2015;72(1):19-20. DOI: 10.1016/j.jaad.2014.07.034.

47. Potekaev N.S., Potekaev S.N., Potekaev N.N., ZHukova O.V. Hairy leukoplakia as a marker of HIV infection and AIDS. Klinicheskaya dermatologiya I venerologiya. 2018;17(4):114-118 (in Russ.). DOI: 10.17116/klinderma201817041114. EDN: YLTJSP.

48. Pham P., Shah M. The Bartlett Pocket Guide to HIV/AIDS Treatment 2021. Ppham and Jbriggs LLC. The United States of America. 2021. 81 p.

49. Crosetti E., Succo G. Non-human immunodeficiency virus-related Kaposi's sarcoma of the oropharynx: a case report and review of the literature. J Med Case Rep. 2013;7:293. DOI: 10.1186/1752-1947-7-293.

50. All-Russian public organization "Russian Society of Dermatovenerologists and Cosmetologists". Federal clinical guidelines for the management of patients with Kaposi's sarcoma. Moscow, 2015. 7 p. (in Russ.)

51. Reid E., Suneja G., Ambinder R.F., Ard K., Baiocchi R., Barta S.K., Carchman E., Cohen A., et al. AIDS-related Kaposi sarcoma, version 2.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2019;17(2):171-189. DOI: 10.6004/jnccn.2019.0008.

52. Sousa R.H., Souza L.L., Guedes P.T., Prado-Ribeiro A.C., Rodrigues-Oliveira L., Brandão T.B., Alves B.W., Lopes M.A., et al. Oral Kaposi sarcoma development is associated with HIV viral load, CD4+ count and CD4+/CD8+ ratio. Med Oral Patol Oral Cir Bucal. 2021;26(6):e748-e753. DOI: 10.4317/medoral.24708.

53. Dubrow R., Qin L., Lin H., Hernández-Ramírez R.U., Neugebauer R.S., Leyden W., Althoff K.N., Achenbach C.J., et al. North American AIDS cohort collaboration on research and design of the international epidemiologic databases to evaluate AIDS. Association of CD4+ T-cell count, HIV-1 RNA viral load, and antiretroviral therapy with Kaposi sarcoma risk among HIV-infected persons in the United States and Canada. J Acquir Immune Defic Syndr. 2017;75(4):382-390. DOI: 10.1097/QAI.0000000000001394.

54. Poizot-Martin I., Lions C., Antoine C., Rey D., Duvivier C., Jacomet C., Allavena C., Huleux T., et al. Kaposi sarcoma in people living with HIV: incidence and associated factors in a French cohort between 2010 and 2015. Wolters Kluwer Health. 2020;34(4):569-577. DOI: 10.1097/QAD.0000000000002450.

55. Caby F., Guiguet M., Weiss L., Winston A., Miro J.M., Konopnicki D., LeMoing V., Bonnet F., et al. CD4/CD8 ratio and the risk of Kaposi sarcoma or non-hodgkin lymphoma in the context of efficiently treated human immunodeficiency virus (HIV) infection: a collaborative analysis of 20 european cohort studies. Clin Infect Dis. 2021;73(1):50-59. DOI: 10.1093/cid/ciaa1137.

56. Uchoa D.C., Pontes F.S., Souza L.L., Santos G.S., Prado-Ribeiro A.C., Brandao T.B., Oliveira L.R., Gomes C.C., et al. HIV-related non-Hodgkin lymphomas affecting the oral cavity: a clinicopathologic study of 11 cases. Med Oral Patol Oral Cir Bucal. 2022;27(2):e99-e105. DOI: 10.4317/medoral.24993.

57. Corti M., Villafañe M.F., Solari R., De Carolis L., Cangelosi D., Santoro J., Schtirbu R., Lewi D., et al. Non-Hodgkin lymphomas of the oral cavity in AIDS patients in a reference hospital of infectious diseases in Argentina: report of eleven cases and review of the literature. J Gastrointest Cancer. 2011;42(3):143-148. DOI: 10.1007/s12029-010-9173-9.

58. SHostakovich-Koreckaya L.R., Litvin K.YU., Kushnerova E.A., Belokon' A.A., Lesnichaya A.A., Margitich I.N. Thecourse of Epstein-Barrne Hodgkin's lymphoma associated patients with HIV with different therapeutic tactics: clinical cases. Klinicheskaya infektologiya i parazitologiya. 2018;7(4):508-517 (in Russ.). EDN: POOWOU.

59. Malek R., Gharibi A., Khlil N., Kissa J. Necrotizing ulcerative gingivitis. Contemp Clin Dent. 2017;8(3):496-500. DOI: 10.4103/ccd.ccd_1181_16.

60. Ravi J.R., Rao T.R. Estimation of prevalence of periodontal disease and oral lesions and their relation to CD4 counts in HIV seropositive patients on antiretroviral therapy regimen reporting at District General Hospital, Raichur. J Indian Soc Periodontol. 2015;19(4):435-439. DOI: 10.4103/0972-124X.156886.

61. Sontakke S.A., Umarji H.R., Karjodkar F.Comparison of oral manifestations with CD4 count in HIV-infected patients. Indian J Dent Res. 2011;22(5):732. DOI: 10.4103/0970-9290.93470.

62. Bravo I.M., Correnti M., Escalona L., Perrone M., Brito A., Tovar V., Rivera H. Prevalence of oral lesions in HIV patients related to CD4 cell count and viral load in a Venezuelan population. Med Oral J. 2009;11(1):E33-39.

63. Lomelí-Martínez S.M., González-Hernández L.A., Ruiz-Anaya A., Lomelí-Martínez M.A., Martínez-Salazar S.Y., Mercado González A. E., Andrade-Villanueva J.F., Varela-Hernández J.J. Oral manifestations associated with HIV/AIDS patients. Medicina. 2022;58:1214-1218. DOI: 10.3390/medicina58091214.

64. Fonseca R.R., Carvalho C.A., Rodrigues T.M.S., Cavaleiro R.M.S., Menezes S.A.F., Machado L.F.A. Severe necrotizing periodontitis in an HIV-Infected patient: case report and non-surgical treatment. Clin Adv Periodontics. 2021;11(2):59-63. DOI: 10.1002/cap.10105.

65. Hu J., Kent P., Lennon J.M., Logan L.K. Acute necrotising ulcerative gingivitis in an immunocompromised young adult. BMJ Case Rep. 2015;20(3):147-150. DOI: 10.1136/bcr-2015-211092.

66. Kato H., Imamura A. Unexpected acute necrotizing ulcerative gingivitis in a well-controlled HIV-infected case.Intern Med. 2017;56(16):2223-2227. DOI: 10.2169/internalmedicine.8409-16.

67. Esayan L.K., Azatyan V.Yu. The study of the prevalence of damage to hard tissues of teeth and periodontal disease in patients with HIV infection. Problemy stomatologii. 2018;14(3):17-21 (in Russ.). DOI: 10.18481/2077-7566-2018-14-3-17-21. EDN: YOGTTF.

68. YelenskayaYu.R., Sakharuk N.A., Grechikha A.S. HIV infection: manifestation in the oral cavity and its prevention. Stomatologiya. Estetika. Innovacii. 2019;3(1):67-75 (in Russ.). EDN: ZSKCVG.

69. Mwau M., Danda J., Mbugua J., Handa A., Fortunko J., Worlock A., Nair S.V. Prospective evaluation of accuracy of HIV viral load monitoring using the Aptima HIV Quant Dx assay with fingerstick and venous dried blood spots prepared under field conditions in Kenya. PLoS One. 2021;16(4):e0249376. DOI: 10.1371/journal.pone.0249376.

70. Mapangisana T., Machekano R., Kouamou V., Maposhere C., McCarty K., Mudzana M., Munyati S., Mutsvangwa J., et al. Viral load care of HIV-1 infected children and adolescents: a longitudinal study in rural Zimbabwe. PLoS One. 2021;16(1):e0245085. DOI: 10.1371/journal.pone.0245085.